Selection and Evaluation of Clinical Investigators: What Really Counts?
(Tami) Phuong Tran (B.SC.)
Student of KRC – Clinical Research Associate Training Program
Abstract
Successful clinical studies will acknowledge the complexity of carrying out a scientific task involving human subjects. The principles involved as well as the respect for the rights of the subjects need to be recognized at all times. Therefore, the clinical investigator responsible for carrying out the study must possess a degree of knowledge, experience and practice. Not only is this an important requirement, but also involving minorities in the clinical study. The process of choosing a clinical investigator to run a clinical trial may be a daunting task. How can one know what to look for in a clinical investigator and what really counts? This article will examine the different areas on what to look for in a clinical investigator, provided with examples.
Introduction
Clinical trials have become more complex in which standards and regulations that must be met are now more crucial then ever. Government officials such as the International Review Board (IRB) and Food and Drug Administration (FDA) are closely monitoring clinical trials. Regulations and guidelines must be followed in order for a clinical trial to be successful. It is highly important to protect the rights and welfare of all clinical trial subjects. Therefore, one of the utmost important factors involving the success of a clinical research trial lies amongst the selection and evaluation of a clinical investigator. Clinical investigators perform the actual research used to support applications for new drugs, biologics and medical devices. A clinical investigator may be a professional researcher operating out of a research institution such as a research hospital or university, or may be a practicing physician who also conducts clinical research. (1) A company in the process of developing new drugs, biologics or medical devices will therefore hire a clinical investigator to carry out the trial by recruiting subjects, conduct the research and report the results back to the company.
The individual(s) involved with the process of selecting and evaluating the clinical investigator must possess the skills and knowledge in the clinical research area in order to know what to look for. What really counts in the selection and evaluation of the clinical investigator? Looking into different key areas and qualities in which a successful investigator candidate should possess can make a clinical trial run more smoothly. Proper selection of clinical investigators is perhaps the single most important factor in the success of a clinical trial. (2). A highly desirable clinical investigator should have knowledge in the research area, possess positive research practices and ethics, will be unbiased to the trial and be involved with the minority society. A minority researcher may also be a desirable candidate as a clinical investigator due to the ties they may have with ethnic communities.
Company or Sponsor Responsibility
Before beginning a clinical research trial, who in the company is responsible for the selection of the clinical investigator? When pharmaceutical companies come up with a new drug or medical device it will need to go through research before the approval process can take place. Usually the sponsor of the company will be in charge of handling this matter. The sponsor is responsible for selecting the investigator(s)/institution(s). (3) They may take on the duty themselves or assign the task to the clinical research associate or other staff. A sponsor can transfer any or all of itâ?Ts obligations, including the monitoring of clinical investigators, to a contract research organization. (1) Whomever is in charge of the selection process will therefore need to follow certain guidelines. Selecting and evaluating a clinical investigator involves recognition of those with potential whom are able to carry out a successful clinical trial. The individual with this responsibility must choose investigators with the necessary experience for the trial, a sufficiently large target population, and a commitment and motivation to steadily and rapidly enroll patients in the study. Finding the right investigators is a delicate balancing act requiring specialized knowledge, years of experience, and a pinch of intuition. (2) It is therefore important that if a sponsor does select another individual to carry out the task of selecting the clinical investigator, then they should wisely choose an experienced individual, staff or contract research organization. If the sponsor assigns this task to another individual, they are still held responsible for overlooking the whole process of the clinical trial.
Knowledge & Experience
The first area to examine when selecting and evaluating a clinical investigator is to determine if they have knowledge and experience in the research area. The clinical investigator that should be chosen for a clinical research trial will have done some studies that are related to the trial, are specializing in the field or a similar field of the study. Potential investigators need to have knowledge in the types of trials that they monitor. A researcher should â?oownâ?ť the science related to a diagnosis to be investigated. (4) They need to understand the background of the particular drug, device or material they are to be dealing with. They should also be familiar with the science related to the action of an intervention. (4) Not only is knowledge in the field important, but also knowledge that is necessary to manage and conduct clinical trials. This knowledge includes the basic fundamentals of conducting the clinical trial, including knowledge of the US regulations and ICH GCPs, as well as the rudiments of organizing a practice to properly conduct trials. (5) It is also highly desirable for the clinical investigator to have had successful completion of a training program, although it is not required by FDA at the moment. It is highly desirable that an investigator is trained because of noncompliance that have been reported. The United States Food and Drug Administration (FDA) and the Department of Health and Human Services (DHHS), and other regulatory agencies around the globe have observed a dramatic increase in noncompliant practices among clinical investigators. (5) Noncompliance can have a negative effect on the success of a clinical research trial. This has caused companyâ?Ts and sponsors to be more stringent on the selection process. For example, some companies now require or will soon require that clinical investigators obtain GCP/ICH (International Conference of Harmonization) training so that such noncompliance will not occur. A clinical investigator that is certified and has gone through training will not only prove that they are knowledgably in running clinical trials, but they will also have a competitive edge amongst other researchers. They will be more desirable to the research companies.
Research Practices & Ethics
The next area that should be examined when selecting and evaluating a clinical investigator is positive research practices and ethics. It is important that clinical investigators carry out good research practices while making appropriate ethical decisions. Investigators should show that they are committed to promoting and advancing the highest ethical standards and practices. (6) They should maintain their compliance throughout the study. Successful completions of clinical trials will depend on these factors and also their strive of excellence. Thus, an investigator must commit to the following responsibilities when agreeing to do a trial:
* Conduct the study according to the protocol.
* Comply with the regulations.
* Personally conduct or supervise the trial.
* Obtain informed consent from subjects.
* Report adverse experiences properly
* Read and understand the material in the investigator brochure before starting the trial.
* Assure that other people assisting in the trial are aware of their obligations. (5)
The clinical investigator must show that they are able to make ethical decisions that can otherwise jeopardize a study. This requires a lot of experience and common sense in knowing what the best decision would be in a given situation. Research in human subjects is governed by FDA regulations that are written almost exclusively for the purpose of ensuring patient safety. According to the Code of Federal Regulations (21 CFR 312.60), â?oan investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigatorâ?Ts care, and for the control of drugs under investigation.â?ť (7) This regulation is basically dictating procedures for investigators to follow and it may seem that all aspects of research conduct would appear to be governed. But the truth of the matter is, is that there are many legal vagaries or â?ogray areasâ?ť that allow the investigators freedom in which to conduct their trials. The existence of these â?ogray areasâ?ť, thus creates a latitude of options in which how the investigator decides what is the best treatment for their patients without limiting their healthcare options. However, the investigators may also be faced to make critical decisions in trials in which they are paid to recruit and retain trial subjects.
The legal vagaries and â?ogray areasâ?ť in which the clinical investigator are free to make decisions can affect a study if the right ethical choices were not chosen. Investigators should not be persuaded into faulty actions due to the benefits that they may receive in completing a clinical trial or maintaining a number of subjects. They need to be able to enter into a trial with known certainty that they will only make the best ethical decisions. An example of how they should make an ethical decision is the options in treatment a patient receives. Should the investigator discover that one treatment is of superior therapeutic merit, he or she is ethically obliged to offer that treatment. (8) The investigator should have no â?otreatment preferenceâ?ť when they believe that there is a more beneficial treatment for that subject. Keeping a subject on the trial knowing that they can receive better treatment is unethical and can put the subjects health at risk. Treatment preference is an example that would fall under a â?ogray areaâ?ť and there are no guidelines in the Code of Federal Regulations (21 CFR312.60), therefore this decision is solely based on the clinical investigator. Clinical investigators should always keep the subjects best interest in mind and ensure patient safety while making decisions, especially if they fall under a â?ogray areaâ?ť category.
Many other legal vagaries and â?ogray areasâ?ť exist when conducing a clinical research trial.
The Clinical Investigator or also known as the Principle Investigator (PI) is the one whom is in charge of conducting the research trial and or is the one to supervise those who do. It is unlikely that the investigator will carry out the whole trial on his/her own and will therefore hire coordinators or even subinvestigators to carry out parts of the research. They hire coordinators to screen patients, conduct rudimentary procedures, dispense study medications, perform selected patient assessments, collect medical histories, and record adverse events. (7) There are no current regulations that require coordinators to be specifically trained or have expertise to carry out such tasks. Therefore, the tasks delegated to the coordinators are left to the discretion of the clinical investigator. The desirable investigator will be able to designate a coordinator with experience and proper handling of study procedures. The coordinators level of experience, training, and education should be of efficient standards for a successful clinical trial. It would be unethical to hire a coordinator knowing that they do not have the proper knowledge to carry out the various duties involved when coordinating a clinical trial.
In addition to clinical investigators hiring coordinators, they frequently designate subinvestigators. Most often, â?osubsâ?ť are physicians or, in the case of teaching hospitals, medical residents (although there is no requirement that they have specific training or expertise). These individuals are appointed to act as the PIs surrogates, and they work with the coordinators just as the PI would. Patients commonly assigned to physicians serving as subs rarely have any contact with the principal researcher. Of course, the requirement that PIs supervise those working on clinical trials remains, but there is no regulatory definition for what constitutes supervision. (7) This leaves clinical investigators with somewhat little regulatory guidance and thus must be cautious when choosing, training and supervising subinvestigators after delegating responsibilities to them. If subinvestigators are not properly chosen then these decisions can directly affect patient care; they are not just administrative or financial choices, but, in fact, ethical considerations. (7) It is important that a clinical investigator ensures good clinical practice compliance, not just for regulatory reasons, but to reduce the companyâ?Ts risk from potential adverse publicity or patient lawsuits. (2) The company or sponsor should thus take research practices and ethics into consideration when selecting and evaluating a clinical investigator. Potential clinical investigators should be able to make the most ethical decisions when dealing with legal vagaries or â?ogray areasâ?ť.
Bias & its Effects
Another aspect that must be considered when selecting and evaluating a clinical investigator for a clinical trial is that they remain unbiased throughout the research. This is an important factor for a successful trial due to the negative consequences that may be caused if bias was present. FDA may consider clinical studies inadequate and the data inadequate if, among other things, if appropriate steps have not been taken in the design, conduct, reporting and analysis of the studies to minimize bias. (9) It is important that investigators are unbiased because conflicting interests may influence the outcome of the study. It can influence the way they carry out a study and also interfere with the protection of human subjects. Therefore, for these reasons it is in the company or sponsorâ?Ts best interest to carefully examine whom they hire as a clinical investigator and make sure that bias does not interfere with the investigatorâ?Ts decision.
What is bias? According to the glossary index of Elsevier, bias is defined as when a point of view prevents impartial judgment on issues relating to the subject of that point of view. (10) There are different types of scenarios in which bias can arise that should be looked at in the evaluation of a clinical investigator. The company and/or sponsor must be able to identify the possible situations. First of all, a desirable investigator should have no Significant Financial Interest connected to the study. Significant Financial Interest means anything of monetary value, including but not limited to, salary or other payments for services (e.g., consulting fees or honoraria); equity interests (e.g., stocks, stock options or other ownership interests); and intellectual property rights (e.g., patents, copyrights and royalties from such rights). (9) It is important that potential clinical investigators do no receive significant amounts of financial interest causing them to be persuaded by that interest. This type of bias may only cause a clinical trial results to be unreliable data and thus an ending in an unreliable study.
An example of financial bias that may arise is that the clinical investigator will get paid a substantial amount from sponsors or companies for enrolling their patients into trials. This situation will raise questions about conflict of interest because it is not known if the investigator is truly enrolling the patient for the patientâ?Ts benefit or for their own financial interest. Clinical investigators are also paid for opening their patientsâ?T confidential records so recruiters can hunt for eligible subjects. Patients are often unaware that their doctors are paid to recruit them for trials. (11) Many situations which clinical investigators are faced with put them in very difficult positions. They must try to win and retain their clinical trial contracts with the industry, but they must also find participants quickly being persuaded by the financial interests they receive. This pressure leads them to their patients confidential records, which is not only a form of bias but it is also unethical.
Another situation that may arise due to bias is that the clinical investigator will carry out a study so that a favorable outcome rather then an unfavorable outcome will result in greater compensation. This compensation can be in the form of equity interest in the sponsor of a covered study or in the form of compensation tied to sales of the product, such as royal interest. (9) They may have a financial interest resulting in the products patent, trademark, copyright or licensing agreement also known as propriety interest in the tested products. One aspect concerns trading in pharmaceutical company shares by investigators who may have premature or inappropriate communication of research results. Investigators may enter patients who have borderline selection criteria into studies, or fabricate results, or induce patients to enter by offering remuneration or better medical care. (11) Companies and sponsors need to be aware that bias in investigators may alter a clinical trialâ?Ts true outcome and therefore should be aware of this fact. They need to be cautious if the investigator has any type of significant financial interest in the study and therefore need to be cautious of what they offer to the clinical investigator.
There are ways to prevent bias. Companies that hire clinical investigators may require them to sign a disclosure agreement under an organizationâ?Ts conflict of interest policy. This will help minimize bias because clinical investigatorâ?Ts payments will be reported if it is of significance. This step taken will also help in determining if the clinical study was inadequate by FDA. The relationship between a sponsor and investigator to be productive and scientifically successful can only exist if conflict and investigator bias are stringently avoided.
Below is a guideline that is ideal for an investigator and sponsor to follow, so that bias can be avoided:
Investigator-Sponsor Relationship
1. The investigator should avoid even the appearance of conflict of interest that could compromise the investigatorâ?Ts professional integrity; the investigator should be vigilant to such potential conflicts.
2. Investigators should not have relationships with industry that could affect their objectivity as a researcher. As such they should not have direct or indirect financial interest in biomedical companies that are active in the investigatorâ?Ts area of research interest. Investigators also should not accept gifts or incentives from such companies, and should avoid paid consulting relationships with the companies for which they also serve as an investigator evaluating a company product.
3. Whenever financial relationships between investigators and sponsor exist, they should be fully disclosed to journals or other publications, medical audiences, and other relevant parties. (12)
These guidelines, if followed by the clinical investigator will not only benefit the investigator and industry but also the clinical trial subjects. The safety of the clinical trial subjects and overall outlook of the clinical trial will not be affected due to bias.
The Minority Investigator & Minority Subjects
Another area to consider when selecting and evaluating a clinical investigator for a successful clinical research study is minority researchers. Minorities make up a large percentage of the population but are underrepresented. The under representation of minorities in clinical trials resulted in a 1993 congressional mandate that led to the NIH policy on inclusion of women and minorities in clinical research. (13) Promoting the inclusion of minorities in clinical trial research is important because the United States has one of the most ethnically diverse populations in the world. A third of the current U.S. population belongs to minority groups, and this proportion is expected to increase steadily. (13) Many factors affect the enrollment of minorities in clinical trials such as attitude, cultural beliefs, social issues, and investigative behavior. The selection of a minority researcher may be a key access to the minority population. Information gathered from the minority population can be essential for the implementation of health policies and interventions for the future.
The importance of minority research is crucial for the needed interventions of high disease rates occurring in minorities. Diabetes has reached epidemic proportions in many minority populations. In virtually every minority group in the United States, diabetes prevalence is greater than in the majority white populations. (14) If studies are not done involving the drug interactions with minorities than it may be more difficult to find a cure or treatment.
An example how minority researchers can be a key access to the minority population is location. Researcherâ?Ts facilities are usually located in the same demographic areas as the minorities. They may work in settings that are in terms for minority representation. Minority subjects are also more likely to choose minority physicians because they feel more comfortable.
Minority researchers are important to clinical trials because they offer cultural empathy, which acts as a bridge to minority participants. Minority researchers know the communities that are advocates for minority populations and have negotiated good relationships with organizations that offer access points to these minority populations. Strong bonds with community-based organizations can lead to partnerships to enhance not only enrollment but also retention and involvement. (13) Minority participants are more likely to feel at ease when in a trial with a researcher they trust. They may also be more open to participate in future clinical studies.
Minority investigators can be of great benefit to the pharmaceutical industry for many reasons. Thus, the inclusion of minorities in clinical studies will result in a more thorough and efficient study. Some general principles and elements that must be present to promote the inclusion of minorities in clinical research are as follows:
* Existence of active links with grassroots organizations
* Outreach and awareness of the cultural component that leads to minority-relevant research
* Knowledge of motivations for participation, that is, the perceived value of the study, the altruistic component, the desire for peer interaction, and assess to care
* Education importance and rationale for participation in clinical trials
* Accessible sites and convenient hours
* Knowledge of the role of the family in decisionmaking (13)
These principles are key to minority involvement because of the barriers that exist in promoting minority inclusion. Investigators must be able to recognize the obstacles and develop approaches in which they can overcome them. They must find ways to make minority participation more accessible. Investigators must also be able to understand the target population. An understanding of the target population is essential if an investigator is to succeed in recruiting that population. The first step is to identify and characterize the population of interest within the community in which it resides. The size of the community, the geography of the area from which the study sample will be drawn, the size of the target population, its demography and history, and where it resides are important starting points. This information is required to estimate whether there are sufficient individuals with the appropriate basic characteristics for the research and whether travel to the research site might be a challenge. (14)
Understanding the target population usually requires more than identifying and characterizing. This is barely sufficient information and additional information will be needed. Examples of additional information that is usually essential include knowledge of ethnic characteristics, cultural customs and norms, socioeconomic level, language, education, literacy, health beliefs and knowledge, and needs and values, including economic, political and religious. Although most researchers will recognize their importance when made aware of these issues, researchers often fail to recognize these factors during the planning process. Researchers put inadequate effort into learning more about the target population, particularly when compared with the effort they put into learning more about the scientific background for the study. (14) Thus a desirable clinical investigator should have done all their proper studying of the target population in order to be successful at recruiting minorities.
If a minority researcher does put in the effort to learn about the target population, they can be of benefit because they can be mentors to minority students whom would otherwise be reluctant to choose clinical research as a profession, especially due to the lack of financial incentives. The lack of financial incentives in clinical medicine is greater than in basic or clinical biomedical research. Instead of careers in research, minority physicians often enter private practice and become active in community affairs. (13) By role modeling and mentoring, minority researchers can thus foster and promote increasing numbers of minority researcher and primary investigators for future clinical trials.
Conclusion
The selection and evaluation of a clinical investigator involves many aspects to take into consideration. Main factors and areas of interest must be incorporated into this decision making process. The proper selection of the clinical investigator starts with the skilled and knowledgeable selector. It is important that a trained professional if not the sponsor themselves, than a contract research organization, clinical research associate or staff to carry out the evaluation and selection tasks. They should be familiar with the different key areas and know what to look for in a potential clinical investigator.
The different areas to look at in a potential clinical investigator is knowledge in the research area. An investigator that is not familiar with the research area cannot perform efficiently due to the lack of knowledge. They may put their subjects at risk which would be unethical. Investigators should also possess positive research practice and ethics. Knowing how to make the right decisions that involve legal vagaries or â?ogray areasâ?ť can be of great benefit to the trial. Also, investigators should avoid bias relating to the research trial. They should avoid any significant financial interest and not be persuaded into faulty actions. Last of all, the importance of involving minorities in clinical studies can be essential for future implementation of health policies and intervention. Therefore, it is highly desirable to consider minority researchers in the selection and evaluation process of a clinical investigator.
References
1. http://oig.hhs.gov/oei/reports/oei-05-99-00350.pdf
2. http://www.devicelink.com/mddi/archive/02/11/015.html
3. http://www.paho.org/english/ad/ths/ev/gcpensponsorresp.pdf
4. http://www3.us.elsevierhealth.com/promo/LaFleur/pdfs/clinicalResearchTerminology.pdf
5. http://www.diahome.org/content/Events/Clinical_Investigator_Guide.pdf
6. http://www.acrpnet.org/certification/fda/cti/fdactibro.pdf
7. http://pubs.acs.org/subscribe/journals/mdd/v04/i04/html/MDD04DeptClinical.html
8. http://content.nejm.org/cgi/content/abstract/317/3/141
9. http://www.uab.edu/irb/aahrpp/iii1a.pdf
10. http://www3.us.elsevierhealth.com/promo/LaFleur/pdfs/clinicalResearchTerminology.pdf
11. http://www.issuesinmedicalethics.org/084or119.html
12. http://www.saem.org/download/edward.pdf
13. http://www.niaid.nih.gov/healthdisparities/HDSYMPOSIUM/proceedings2/session2.htm
14. http://journal.diabetes.org/diabetesspectrum/98v11n3/pg161.htm
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